Process for producing 2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4] non-1-en-4-one

ABSTRACT

Disclosed herein a process for producing 2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one of formula (I) in pure form by using selective solvent system and cost efficient raw materials and reagents.

FIELD OF THE INVENTION

This invention, in general, relates to a process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(Irbesartan). In particular the present invention provides a novelprocess for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-onein pure form by using selective solvent system and cost efficient rawmaterials.

BACKGROUND OF THE INVENTION

2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(Irbesartan) is represented by Formula I.

Irbesartan is a powerful angiotensin II receptor antagonist (blocker).Angiotensin is an important participant in therenin-angiotensin-aldosterone system (RAAS) and has a strong influenceon blood pressure.

Many processes are disclosed in the art for the preparation ofIrbesartan. Irbesartan has been generally prepared as per the processdisclosed in EP-A-0 454 511, i.e. by reaction of2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneeither with tributyltin azide and triphenyl chloromethane in xylene atreflux, by elimination of the triphenylmethyl protecting group and byisolation from a solution in ethyl acetate, duly dried. The othercommonly used process is disclosed in C. A. Bernhart et al., J. Med.Chem., 1993, 36, 3371-3380. The process involves reaction of2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-onedirectly with tributyltin azide, in xylene at reflux and isolation froma solution in dichloromethane, duly dried. The compound thus prepared,[Formula (I)], is presented in the form of stable, non-hygroscopicneedles, which can be stored and formulated without any degradation.

U.S. Pat. Nos. 5,196,444 and 5,399,578 and describe similar proceduresfor the synthesis of some non-peptide angiotensin II inhibitors whereinthe use of trimethyltin azide is reported in presence of toluene as asolvent for the conversion of aromatic nitrles into tetrazoles. Allthese processes require trialkyltin azide as a reagent, which is notsafe to handle and is costly. The reaction time is usually long, rangingfrom 36 hours to 4 days. The isolation of product from such reactionmixtures can be tedious, requiring several critical layer separations,and the yield obtained is generally low.

U.S. Pat. No. 5,629,331 describes a process for the preparation ofIrbesartan Form A and B wherein the aromatic nitrile is treated withsodium azide in presence of triethylamine hydrochloride in1-methylpyrrolidin-2-one as solvent at a temperature of 121-123° C. Thesolvent used is costly and not easily recovered, making the processunsuitable for commercial scale production.

U.S. Pat. No. 6,162,922 has described a process for the preparation ofIrbesartan which involves treating the Spiro intermediate of Formula IIIwith halomethyl cyanobiphenyl intermediate of Formula IV in presence ofa water and water immiscible solvent, a base and a phase transfercatalyst.

The processes known in the prior art for preparing Irbesartan involvetedious workup procedures, e.g., a large number of steps, which includethe protection and subsequent deprotection, and isolation ofintermediates, as well as separations by column chromatography. Theprocesses of the art involve tedious workup to isolate the requiredproduct and this results in excessive production times, which in turnrenders the process more costly and less eco-friendly; thus theprocesses are not suitable for commercial scale up. Accordingly, thereremains a need for a simple, commercially advantageous process.

SUMMARY OF THE INVENTION

It is a principal object of the present invention to provide anindustrially viable process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I employing selective solvent system and cost efficient rawmaterials.

Another object of the present invention is to provide an industriallyviable process for producing2-(n-butyl)-3-[[′-(tetrazol-1-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, wherein the solvents used in the process are recoverableand reusable.

Further object of the present invention is to provide an industriallyviable process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, wherein the process employs condensation reaction usingselective solvent system in presence of a base to prepare anintermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II with good yield and purity to produce said compound ofFormula I.

Yet another object of the present invention is to provide anindustrially viable process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, wherein said intermediate of Formula II is optionallypurified employing selective solvent, avoiding the use of columnchromatographic purification.

Yet another object of the present invention is to provide anindustrially viable process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, wherein said compound of Formula I is obtained by simplecrystallization employing a selective solvent to avoid multiplepurification steps.

The above and other objects are attained in accordance with the presentinvention wherein there is provided following embodiments, however thedescribed embodiments hereinafter is in accordance with the best mode ofpractice and the invention is not restricted to the particularembodiments.

In accordance with one preferred embodiment of the present invention,there is provided a process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I comprising condensing2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one of Formula III or acidaddition salt thereof with 4-(bromomethyl)-2′-cyanobiphenyl of FormulaIV in the presence of base and mixture of solvents to get anintermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II, treating the intermediate of Formula II with azide in thepresence of organic base and organic acid and optionally employing asolvent, and isolating the final product2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I.

In accordance with one preferred embodiment of the present invention,there is provided a process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof formula I, comprising condensing2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one of Formula III or acidaddition salt thereof with 4-(bromomethyl)-2′-cyanobiphenyl of FormulaIV in the presence of base and mixture of polar aprotic solvent and nonpolar solvents to get an intermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II, wherein said mixture of solvents used herein are selectedfrom the group comprising any organic solvent preferably toluene,xylene, dimethylformamide or dimethyl sulfoxide.

In accordance with one preferred embodiment of the present invention,there is provided a process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, comprising condensing2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one of Formula III or acidaddition salt thereof with 4-(bromomethyl)-2′-cyanobiphenyl of FormulaIV in the presence of base and a mixture of solvents selected from polaraprotic solvent and non polar solvents to get an intermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II, wherein said mixture of solvents used is preferably amixture of dimethylformamide and toluene.

In accordance with another embodiment of the present invention, theintermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II, is optionally purified in presence of mixture of waterand an alcoholic solvent.

In accordance with yet another preferred embodiment of the presentinvention, there is provided a process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, wherein the intermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II is further treated with azide in the presence of organicbase and organic acid and optionally employing a solvent to obtain2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I.

In accordance with yet another preferred embodiment of the presentinvention, there is provided a process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I, wherein the intermediate2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula II is further treated with azide in the presence of organicbase and organic acid and optionally employing a solvent, wherein saidsolvent is selected from aromatic or aliphatic hydrocarbons, ethers,ketones, esters or alcohols or mixtures thereof.

DESCRIPTION OF THE INVENTION

The present invention provides a novel, economical and a high yieldingprocess for the industrial production of2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I employing readily available raw materials and reagents.

The process disclosed according to the present invention does notinvolve any chromatographic purification method for intermediates orfinal product. Also, the use of organotin reagent for the formation oftetrazole from cyano as a starting material, as disclosed in prior art,is avoided. Further, the process is carried out in the presence of asolvent i.e. hydrocarbon which is easily recovered and recycled, therebyproviding the2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I with high quality without using multiple purificationsteps.

The process for producing2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneof Formula I (Irbesartan) is described in scheme 1.

The process involves condensation of2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one of Formula III or itsacid addition salt with 4-(bromomethyl)-2′-cyanobiphenyl of Formula IVin the presence of base and a mixture of polar aprotic solvent and anon-polar solvent, wherein said acid addition salt of Formula III isselected from the group consisting of, but not limited to,hydrochloride, hydro bromide, hydrogen sulfate, preferablyhydrochloride. The base used herein is selected from the groupconsisting of, but not limited to, alkoxide of alkali metal such assodium methoxide, potassium methoxide, sodium tert-butoxide, potassiumtert-butoxide; hydrides of alkali metal such as sodium hydride;hydroxide of alkali metal such as sodium hydroxide, potassium hydroxide,cesium hydroxide; carbonates of alkali metal such as cesium carbonate,potassium carbonate or sodium, carbonate. The preferred base used hereinis hydroxide of alkali metal such as sodium hydroxide, potassiumhydroxide, cesium hydroxide and more preferably sodium hydroxide.

According to the present invention, said condensation reaction iscarried out in a mixture of solvents in the presence of base, and it isfound that the formation of impurities is very less as compared to thecondensation reaction carried out in a single solvent. The solvents usedherein are selected from the group comprising of polar aprotic solventand a non-polar solvent preferably toluene, xylene, tetrahydrofuran,dimethylformamide or dimethyl sulfoxide, more preferably mixture ofdimethylformamide and toluene.

The condensation reaction is carried out at a temperature in the rangeof about 0-60° C., preferably at a temperature in the range of about 25°C.-40° C. After the completion of the reaction, reaction mass is dilutedwith water and aqueous layer is separated from the organic layer andextracted with organic solvent. The combined organic layer is washedwith water, dried and concentrated under reduced pressure to getresidue. The residue can be taken further for reaction with azide orpreferably purified from a mixture of water and an alcoholic solvent toget a compound of Formula II as a solid material with improved yield andhigh purity. The organic solvent used herein selected from the groupcomprising toluene or xylene, preferably toluene and wherein saidalcoholic solvent is selected from methanol, ethanol or isopropylalcohol.

The compound of Formula II is reacted with azide in the presence oforganic base and organic acid and optionally employing a solvent to getcompound of Formula I. The azide used herein is alkali metal azide,preferably sodium azide. The organic base used is triethyl amine. Theorganic acid used herein is selected from C₁-C₄ carboxylic acid,preferably acetic acid.

The solvent used herein is selected from the group comprising aromaticor aliphatic hydrocarbons such as heptane, toluene or xylene, ketonessuch as methyl isobutyl ketone, esters such as n-butyl acetate, etherssuch as dioxane or alcohols such as n-butanol.

The reaction is carried out at a temperature in the range of about 70°C. to 140° C., preferably in the range of about 115° C. to about 130° C.According to the present invention, sodium azide and organicbase/organic acid are used in proportions of 1:1 to 1:6 moles per moleof starting nitrile, preferably 1:2 to 1:4 moles per mole of startingnitrile, more preferably 1:2 mole per mole of starting nitrile. Upon10-25 hours of heating, the reaction is over and the reaction mixture istreated according to the conventional techniques, more particularly, themixture is basified by the addition of base preferably alkalinehydroxide, in aqueous solution. The mixture then separate into threelayers namely, upper organic layer, middle product layer and loweraqueous layer. The aqueous phase containing the salts, particularlychlorides and azides is removed and the oily phase is treated with waterand organic solvent, such as xylene, to eliminate the reactionbyproducts. The resultant aqueous phase, containing the alkaline salt ofthe2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-oneis subjected to acidification, preferably by addition of aqueoushydrochloric acid until the pH is between 2.0 and 4.0, preferablybetween 2.5 and 3.0 to obtain the crude2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one,which is further washed with water and ethyl acetate.

The crude material is recrystallized in from an alcoholic solvent to getIrbesartan in highly pure form.

The following non-limiting examples illustrate specific embodiments ofthe present invention. They are, however, not intended to be limitingthe scope of the present invention in any way.

Example 1 Preparation of2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(II)

A RB flask was charged with2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one (7.0 g), toluene (70 ml),DMF (30 ml) and sodium methoxide (2.2 g) at room temperature and stirredfor 15 min, followed by the addition of 4-(bromomethyl)-2′-cyanobiphenyl(10 g). The reaction mixture was stirred for 1 hour and then quenched bythe addition of water (100 ml). The layers were separated and organiclayer was evaporated to get oily residue. The obtained residue was takenin isopropyl alcohol (10 ml) and water (10 ml) and stirred at roomtemperature to get solid material. The solid material was filtered andwashed with IPA and water mixture and then dried under vacuum.

Example 2

A RB flask was charged with2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one (7.0 g), toluene (70 ml)and DMF (30 ml). 4-(Bromomethyl)-2′-cyanobiphenyl (10 g) and sodiumhydroxide (1.6 g) was added to reaction mixture and stirred at roomtemperature. The reaction was quenched by the addition of water (100ml). Then the layers were separated and organic layer was evaporated toget oily residue, which was taken in isopropyl alcohol (10 ml) and water(10 ml) and stirred at room temperature to get solid material. The solidmaterial was filtered and washed with IPA and water mixture and thendried under vacuum.

Example 3

A RB flask was charged with2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one (7.0 g), toluene (70 ml)and DMF (30 ml), followed by the addition of4-(Bromomethyl)-2′-cyanobiphenyl (10 g). The reaction mixture was cooledto 10-15° C. and then cesium carbonate (13.0 g) was added to it. Thereaction mixture was stirred at room temperature for 1 hour and then thereaction was quenched by addition of water (100 ml). The layers wereseparated and organic layer was evaporated to get oily residue, whichwas taken in isopropyl alcohol (10 ml) and water (10 ml) and stirred atroom temperature to get solid material. The solid material was filteredand washed with IPA and water mixture and then dried under vacuum.

Example 4

A RB flask was charged with2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one (7.0 g), toluene (70 ml)and DMF (30 ml), followed by the addition of4-(Bromomethyl)-2′-cyanobiphenyl (10 g). The reaction mixture was cooledto 10-15° C. and then potassium carbonate (5.0 g) was added to it. Thereaction mixture was stirred at room temperature for 1 hour and then thereaction was quenched by addition of water (100 ml). The layers wereseparated and organic layer was evaporated to get oily residue, whichwas taken in isopropyl alcohol (10 ml) and water (10 ml) and stirred atroom temperature to get solid material. The solid material was filteredand washed with IPA and water mixture and then dried under vacuum.

Example 5

A RB flask was charged with2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one (7.0 g), toluene (70 ml)and DMF (30 ml), followed by the addition of4-(Bromomethyl)-2′-cyanobiphenyl (10 g). The reaction mixture was cooledto 10-15° C. and then potassium tert-butoxide (4.6 g) was added to it.The reaction mixture was stirred at room temperature for 1 hour and thenthe reaction was quenched by addition of water (100 ml). The layers wereseparated and organic layer was evaporated to get oily residue. Theobtained residue was taken in isopropyl alcohol (10 ml) and water (10ml) and stirred at room temperature to get solid material, which wasfiltered and washed with IPA and water mixture and then dried undervacuum.

Example 6 Preparation of2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(I)

A RB flask was charged with n-butyl Acetate (50 ml), triethyl amine (22ml) and acetic acid (9 ml) and stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium Azide (3.4 g) was added to the flask and the reactionmixture was heated at 115-120° C. for 24 hrs, followed by cooling. Thereaction was then quenched by addition of water (30 ml). The pH of theaqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxideand then stirred for 10 min. Layers were separated and oily layer wastreated with water and xylene. The pH of the aqueous layer was adjustedbetween 2 and 3 by the addition of hydrochloric acid and then stirredfor 1 hour, filtered to obtain solid material which was washed withwater (20 ml) and ethyl Acetate (5 ml) and dried at 90-100° C.

Example 7

A RB flask was charged with n-heptane (50 ml), triethyl amine (22 ml)and acetic acid (9 ml) and stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium azide (3.4 g) was added to the flask and the reactionmixture was heated at 100-105° C. for 24 hrs, followed by cooling. Thereaction was then quenched by addition of water (30 ml). The pH of theaqueous layer was adjusted between 10 to 11 with 30% Sodium hydroxideand then stirred for 10 min. Layers were separated and pH of the aqueouslayer was adjusted between 2 and 3 by the addition of hydrochloric acidand stirred for 1 hour, filtered to obtain solid material which waswashed with water (20 ml) and ethyl acetate (5 ml) and then dried at90-100° C.

Example 8

A RB flask was charged with toluene (50 ml), triethyl amine (22 ml) andacetic acid (9 ml) and stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium azide (3.4 g) was added to the flask and the reactionmixture was heated at 1115-120° C. for 24 hrs, followed by cooling. Thereaction was then quenched by the addition of water (30 ml). The pH ofthe aqueous layer was adjusted between 10 to 11 with 30% Sodiumhydroxide and stirred for 10 min. Layers were separated and oily layerwas treated with water and xylene. The pH of the aqueous layer wasadjusted between 2 and 3 by the addition of hydrochloric acid andstirred for 1 hour, filtered to obtain solid material which was washedwith water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100° C.

Example 9

A RB flask was charged with n-butanol (50 ml), triethyl amine (22 ml)and acetic acid (9 ml) and stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium azide (3.4 g) was added to the flask and the reactionmixture was heated at 115-120° C. for 24 hrs, followed by cooling. Thereaction was then quenched by the addition of water (30 ml). The pH ofthe aqueous layer was adjusted between 10 to 11 with 30% Sodiumhydroxide and stirred for 10 min. Layers were separated and oily layerwas treated with water and xylene. The pH of the aqueous layer wasadjusted between 2 and 3 by the addition of hydrochloric acid andstirred for 1 hour, filtered to obtain solid material which was washedwith water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100° C.

Example 10

A RB flask was charged with methyl isobutyl ketone (50 ml), triethylamine (22 ml) and acetic acid (9 ml) and stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium azide (3.4 g) was added to the flask and the reactionmixture was heated at 115-120° C. for 24 hrs, followed by cooling. Thereaction was then quenched by the addition of water (30 ml). The pH ofthe aqueous layer was adjusted between 10 to 11 with 30% Sodiumhydroxide and stirred for 10 min. Layers were separated and oily layerwas treated with water and xylene. The pH of the aqueous layer wasadjusted between 2 and 3 by the addition of hydrochloric acid andstirred for 1 hour, filtered to obtain solid material which was washedwith water (20 ml) and ethyl acetate (5 ml) and then dried at 90-100° C.

Example 11

A RB flask was charged with xylene (50 ml), triethyl amine (15 ml) andacetic acid (6 ml) and stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium azide (3.4 g) was added to the flask and the reactionmixture was heated at 120-125° C. for 24 hrs, followed by cooling. Thereaction was then quenched by the addition of water (30 ml). The pH ofthe aqueous layer was adjusted between 10 to 11 with 30% Sodiumhydroxide and stirred for 10 min. Layers were separated and oily layerwas treated with water and xylene. The pH of the aqueous layer wasadjusted between 2 and 3 by the addition of hydrochloric acid andstirred for 1 hour, filtered to obtain solid material which was thenwashed with water (20 ml) and ethyl acetate (5 ml) and then dried at90-100° C.

Example 12

A RB flask was charged with triethyl amine 22 ml and acetic acid 9 mland stirred.2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one(10 g) and sodium azide (3.4 g) was added to the flask and the reactionmixture was heated at 90-100° C. for 24 hrs, followed by cooling. Thereaction was then quenched by the addition of water (30 ml) and xylene(30 ml). The pH of the aqueous layer was adjusted between 10 to 11 with30% Sodium hydroxide and stirred for 10 min, Layers were separated andoily layer was treated with water and xylene. The pH of the aqueouslayer was adjusted between 2 and 3 by the addition of hydrochloric acidand stirred for 1 hour, filtered to obtain solid material which was thenwashed with water (20 ml) and ethyl acetate (5 ml) and then dried at90-100° C.

While this invention has been described in detail with reference tocertain preferred embodiments, it should be appreciated that the presentinvention is not limited to those precise embodiments. Rather, in viewof the present disclosure, which describes the current best mode forpracticing the invention, many modifications and variations wouldpresent themselves to those skilled in the art without departing fromthe scope and spirit of this invention.

1. A process for producing purified2-(n-butyl)-3[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one,comprising: (a) condensing2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one or an acid addition saltthereof with 4-(bromomethyl)-2′-cyanobiphenyl of in the presence of abase, wherein the base comprises at least one alkoxide, hydride,hydroxide or carbonate of an alkali metal, and a mixture of solventscomprising at least one polar aprotic solvent and at least one non-polarsolvent, wherein the solvents in the mixture of solvents are selectedfrom the groups consisting of polar aprotic and non-polar solvents, toproduce2-(n-butyl)-3[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one,which is purified in presence of mixture of water and an alcoholicsolvent; (b) treating the purified2-(n-butyl)-3[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-onewith azide in the presence of an triethyl amine and acetic acidemploying a solvent medium, wherein the solvent medium comprises atleast one solvent selected from the group consisting of aliphatichydrocarbons, ketones, esters, ethers, alcohols, toluene and xylene, toproduce2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one;and (c) isolating the2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4,4]non-1-en-4-oneemploying an organic solvent, to obtain the purified2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.2. The process according to claim 1, wherein the acid addition salt is ahydrochloride, hydro bromide or hydrogen sulfate of the2-(n-butyl)-1,3-diazaspiro[4,4]non-1-ene-4-one.
 3. The process accordingto claim 1, wherein the base comprises sodium methoxide, potassiummethoxide, sodium tert-butoxide, potassium tert-butoxide, sodiumhydride, sodium hydroxide, potassium hydroxide, cesium hydroxide, cesiumcarbonate, potassium carbonate or sodium carbonate.
 4. The processaccording to claim 3, wherein the base comprises sodium hydroxide orpotassium hydroxide.
 5. The process according to claim 1, wherein thesolvents in the mixture of solvents are selected from the groupconsisting of toluene, xylene, dimethylformamide, dimethyl sulfoxide andmixtures thereof.
 6. The process according to claim 1, wherein themixture of solvents comprises toluene and dimethylformamide.
 7. Theprocess according to claim 1, wherein the alcoholic solvent comprisesmethanol, ethanol or isopropyl alcohol.
 8. The process according toclaim 1, wherein the solvent medium is selected from the groupconsisting of n-heptane, methyl isobutyl ketone, n-butyl acetate,dioxane, n-butanol and mixtures thereof.
 9. The process according toclaim 1, wherein the organic solvent is selected from the groupconsisting of methanol, ethanol, isopropyl alcohol and mixtures thereof.10. The process according to claim 1, further comprising treating the2-(n-butyl)-3-[[2′-(cyano)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-onewith an azide in the presence of an organic base and an organic acid andoptionally employing a solvent medium to obtain2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one.11. The process according to claim 1, wherein the solvent mediumcomprises at least one member selected from the group consisting ofaliphatic hydrocarbons, ketones, esters, ethers and alcohols.
 12. Theprocess according to claim 1, wherein the solvent medium is comprises atleast one member selected from the group consisting of n-heptane,toluene, xylene, methyl isobutyl ketone, n-butyl acetate, dioxane andn-butanol.
 13. The process according to claim 8, wherein the solvent isrecoverable and reusable in the process.
 14. The process according toclaim 1, wherein condensation (a) is conducted at a temperature of 0-60°C.
 15. The process according to claim 1, wherein condensation (a) isconducted at a temperature of 25-40° C.
 16. The process according toclaim 1, wherein treatment (b) is conducted at a temperature of 70-140°C.
 17. The process according to claim 1, wherein treatment (b) isconducted at a temperature of 115-130° C.
 18. The process according toclaim 1, wherein (c) comprises recrystallizing the2-(n-butyl)-3-[[2′-(tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3-diazaspiro[4,4]non-1-en-4-onein an alcoholic solvent.